Pharmaceutical formulation for the treatment of inflammatory changes to the rectum

ABSTRACT

Disclosed is a storage-stable pharmaceutical formulation for rectal administration, containing budesonide or a pharmaceutically compatible salt or derivative thereof, and at least 80 wt % of a solid fat or a mixture of different solid fats, based on the total weight of the formulation, as well as at least one anti-oxidation agent that is compatible therewith.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a national stage application under 35 U.S.C. § 371of International Application No. PCT/EP2016/064907, filed 28 Jun. 2016,which claims priority from European Patent Application No. 15175806.7,filed 8 Jul. 2015, which applications are incorporated herein byreference.

Chronic inflammatory diseases of the gastro-intestinal tract arereferred to as the Crohn's disease as well as ulcerative colitis. Theetiology of said diseases is unknown, although an autoimmune aspect ofsaid diseases is often assumed. The disease “Crohn's disease” maycontain a variety of clinical manifestations and said disease can belocated in different parts of the small intestine as well as of thelarge intestine. Ulcerative colitis is an inflammatory intestinaldisease that is substantially confined to the large intestine. Thedisease is characterized by recurrent inflammatory conditions thatprimarily affect the mucosa layer and occasionally also the submucosalayer of the colon. Acute inflammatory conditions are characterized bychronic diarrhoea or constipation, bleeding in the intestinal tract,cramps and stomachache.

Occasionally, a distinction is made regarding ulcerative proctitis,which is regarded as a milder form of ulcerative colitis. For thetherapy of said diseases specifically formulated formulations for oraladministration can be used. However, oral administration may bedisadvantageous due to the diarrhoea often associated with the disease.

In the prior art there are also known rectally administrableformulations. Gross et al., Aliment. Pharmacol. Ther. 2006, 23, 303-312in the treatment of active ulcerative proctitis or proctosigmoiditishave compared budesonide foams with budesonide enemas.

Belluzzi et al. (Gastroenterology, Vol. 104 (4, Suppl.) 1993) havesuggested suppositories with 5-aminosalicylic acid or budesonide. Thebudesonide suppositories used there contained 0.5 mg budesonide and weregiven three times a day. Alternatively, suppositories with 500 mg5-aminosalicylic acid were given three times a day.

U.S. Pat. No. 5,449,520 discloses pharmaceutical compositions for therectal administration, which contain a medicament topically active onthe colon. The rectal foams disclosed there contain as a pharmaceuticalactive ingredient mesalazine or budesonide. WO 2015/073846 describes amethod for the treatment of ulcerative colitis in which a rectal foam isemployed. The foam is an emulsion containing budesonide, propyleneglycol, cetyl alcohol, water, and suitable additives.

In the German utility model DE 297 17 252 there is disclosed a medicaldrug kit of a budesonide-containing and an ursodeoxycholicacid-containing medical drug for the treatment of cholestatic hepaticdiseases. One formulation example relates to budesonide-containingsuppositories, wherein budesonide is suspended in solid fat.

DE-OS 198 49 737 discloses suppositories containing an active ingredientcombination consisting of 5-ASA and budesonide suspended in solid fat.Due to the high proportion of 5-ASA these suppositories have arelatively high weight and thus, also a corresponding size.

A disadvantage of the known pharmaceutical formulations on the one handis that some patients dislike to use enemas or also rectal foams.Another requirement is that a pharmaceutical formulation is desired thatprovides the active ingredient budesonide in a storage-stable form.

It is a task of the present invention to provide a pharmaceuticalformulation of budesonide for the rectal application that isstorage-stable and that allows painless insertion by an optimum form,consistency and suitable size as well as a specific, local andrectum-confined application of the active ingredient.

According to the invention, these criteria are fulfilled by theadministration in the form of turundula also referred to as suppository.Suppositories contain a single dose of the medicinally effectivecomponent budesonide that can be dissolved (solution preparation),emulsified (emulsion preparation) and suspended (suspension preparation)in a lipid-containing or water-soluble preparation.

The pharmaceutical formulations according to the invention are highlystorage-stable. A problem with the provision of suppositories(turundulas) is that when such preparations are stored at roomtemperature or a slightly increased temperature (20-30° C.), which oftenoccurs during the summer months or in warmer areas, thepharmacologically active ingredient budesonide is decomposed tobiologically inactive or less active decomposition products. Theformulations according to the invention are storage-stable over a longerperiod of time (12-24 months) also at an increased temperature (20-30°C.). This means, that after storage over 24 months at 25° C. still atleast 90%, preferably at least 95% and preferably at least 97% of theoriginally employed active ingredient (budesonide) are present in apharmacologically active form.

The present invention relates to a preparation for the rectal use,particularly a suppository, that includes as the therapeuticallyeffective component budesonide or a pharmaceutically compatible salt orderivative thereof and after insertion is used for the treatment ofinflammatory diseases of the rectum (proctitis). In doing so, highdemands must be made on the selection of a suitable basis. This basishas to be chemically stable and inert and therefore highly compatiblewith the medicinally effective component, as well as compatible withmucous membranes and therefore free of mucosal irritation duringapplication. Further, it has to reliably release the intermingledmedicinally effective component at the place of use after application bymelting or dissolving.

Thus, the object of the present invention is a storage-stablepharmaceutical formulation for rectal administration, containingbudesonide or a pharmaceutically compatible salt or derivative thereof,and at least 80 wt % of a solid fat or a mixture of different solidfats, based on the total weight of the formulation, as well as at leastone anti-oxidation agent that is compatible therewith.

In a preferred embodiment of the present invention there is chosen asolid fat composition having a small distance between the melting andfreezing point. The melting point is the temperature at which thesuppository melts. Said melting point is preferably between about 33.5°C. and about 35.5° C., preferably between 34.0° C. and 35.0° C. Thefreezing point is the temperature at which the suppository freezes aftermanufacture, i.e. the point at which the suppository solidifies aftermanufacture. According to the invention, said freezing point ispreferably between about 32.5° C. and 34.5° C., particularly preferred33.0° C. to 34.0° C.

In a preferred embodiment, the solid fat employed according to theinvention has a high proportion of triglycerides that is preferablyabove 80 wt %, particularly preferred above 90 wt %, and especiallypreferred above 95 wt. %.

As a parameter of said solid fats there is known the so-called hydroxylvalue. According to invention the solid fats employed have a lowhydroxyl value that is in the range of from 1 to 15, preferably 5 to 15,and particularly preferred 5 to 10.

A further property of the preferred solid fats is that the proportion ofthe unsaturated fatty acids is less than 1 wt %, particularly preferredless than 0.5 wt %.

The suppositories according to the invention are designed for analadministration. Thus, the form is chosen such that they can beconveniently applied and are considered well acceptable by the majorityof patients because they neither cause pain nor an unpleasant feelingwhen administered. In a preferred embodiment the suppositories have aso-called “torpedo shape”. Also important is the size of thesuppositories that is determined by the total weight of thesuppositories. Preferably, the weight is between 0.8 g and 1.2 g,particularly preferred between 0.95 g and 1.05 g.

In a preferred embodiment the suppository according to the invention asthe active ingredient contains budesonide in an amount between 1.8 mgand 2.2 mg per suppository, preferably between 1.9 mg and 2.1 mgbudesonide per suppository and especially preferred between 1.95 mg and2.05 mg budesonide per suppository.

In another preferred embodiment the suppository according to theinvention as the active ingredient contains budesonide in an amountbetween 3.8 mg and 4.2 mg per suppository, preferably between 3.9 mg and4.1 mg budesonide per suppository and especially preferred between 3.95mg and 4.05 mg budesonide pro suppository.

According to the invention, it is preferred that the suppository as thepharmacologically active ingredient only contains budesonide and noother pharmacologically active component. In particular, thesuppositories according to the invention especially preferred contain no5-ASA (5-aminosalicylic acid). Since 5-ASA itself is oxidation-sensitivethe addition of 5-ASA could result in an undesired brown coloration ofthe suppository.

In a preferred embodiment, the suppositories according to the inventionas the anti-oxidation agent contain ascorbyl palmitate. Theconcentration of the ascorbyl palmitate is preferably 50 ppm to 200 ppm,particularly preferred 125 to 175 ppm, and especially preferred 150 ppm.

A further preferred aspect of the present invention is that thebudesonide is present in a micronized form. Micronized form means thatthe particle size of the active ingredient is very small, wherein 100%of the particles are smaller than 10 μm per particle.

An essential aspect of the present invention is the storage stability ofthe suppositories according to the invention. The storage stability canbe further enhanced by various process steps during manufacture. On theone hand, the manufacture of the suppositories can be carried out underexclusion of oxygen. This can be achieved by nitrogen purge duringmanufacture or working under inert-gas atmosphere.

On the other hand, the melted mass is preferably poured into a blisterfoil during the production of the suppositories, where the hardeningtakes place. In a preferred embodiment the suppositories according tothe invention are packed in a gas-tight film.

It is generally known to use lipid-containing or water-solublepreparations as the basis for suppositories. Preferably, triglyceridesare used as the lipids. Solid fat is a semi-synthetic mixture of mono-,di-, and triglycerides of saturated fatty acids. Starting from palmkernel oil and coconut butter defined solid fats having certain meltingproperties and certain hydroxyl values can be obtained aftersaponification and re-esterification of glycerin with suitable saturatedfatty acids via the ratio of mono-, di-, and triglycerides. Thus, by thechoice of fatty acids and the degree of esterification the properties ofsolid fat can be modified and properties such as melting range,water-absorbing capacity, and brittleness can be influenced. By the lackof unsaturated fatty acids solid fats have better stability propertiesthan cocoa butter, which therefore only plays a minor role as asuppository basis.

The choice of the suitable solid fats plays an important role forachieving the required storage stability. Thus, preferably the solidfats described here are employed, wherein a crucial aspect is to achievethe desired storage stability. To achieve the storage stabilityparticularly also the ratio of budesonide (active ingredient) to solidfat is essential.

The solid fats preferably used according to the invention are based onglycerides of saturated C₁₂-C₁₈ fatty acids. They largely consist oftriglycerides containing not more than 15% of diglycerides and not morethan 1% of monoglycerides. In the manufacture of the solid fatsaccording to the invention at first vegetable fats are decomposed intofatty acids and glycerin after purification by means of water at hightemperature. The fatty acid blend is hydrogenated, fractionated, andvacuum-distilled, above all to remove short-chain fatty acids. TheC₁₂-C₁₈ fatty acids preferably used are adjusted to a suitable blend andesterified with purified glycerin. Said reaction blend is subsequentlyfurther purified, in particular by washing, vacuum drying, treating toremove dyes, and steam distillation. The preferably used hard waxescontain at least 85%, preferably at least 90%, of C₁₂-C₁₈ fatty acidchains. It is also important that the hydroxyl value of the solid fatsis preferably less than about 10. The hydroxyl value is mainly due tothe monoglycerides, since these provide two hydroxyl groups from theglycerol residue, and diglycerides, which have a free hydroxyl group.The hydroxyl value can be measured by determining the amount of KOH thatis required to neutralize the amount of acetic acid that is consumed bythe acetylation of the solid fat. That is, the hydroxyl value denotesthe amount of the free hydroxyl groups in the solid fat basis. Since thesolid fats employed according to the invention are usually releasedduring the purification of glycerin the hydroxyl value is an indicatorfor the presence of mono- and/or diglycerides that are present in thesolid fat blend. Provided that further additives are present in thesolid fat blend that contribute to the free hydroxyl groups they alsoinfluence the hydroxyl value.

A further important characteristic of the solid fats according to theinvention is the iodine value. The iodine value represents the amount ofgrams of halogen (iodine) that is consumed by 100 g of the solid fatblend. For the consumption of halogen unsaturated compounds, i.e.unsaturated fatty acids, are responsible. Since, according to theinvention, this proportion is very low, the iodine number for thequalities to be used is less than 3, preferably less than 2.

An essential parameter of the suppository basis is also the peroxidevalue. This value reflects the amount of peroxide in milliequivalents ofactive oxygen that are present in 1000 g of the suppository basis. Inthe suppository basis used according to the invention the peroxidevalue, given in meq O/kg, is at most 5, preferably at most 3, andparticularly preferred at most 1.

In addition to the lipid-containing suppository bases also water-solublemacrogol-based masses are used that dissolve in the rectally presentliquids. Preferably, macrogol 6000 or blends of high and low molecularmasses are employed. The proportions of macrogol-based additives arebetween 0 and 20, preferably between 0 and 5, and particularly preferredat 0.1 to 3 wt %, based on the finished formulation. If such componentsare used, care must be taken to ensure a low peroxide value of at most 5meq O/kg.

Budesonide is a glucocorticoid having a high local anti-inflammatoryefficacy. The substance is virtually insoluble in water (0.014 mg/ml,Merck Index), however, due to its lipophilic properties appreciableamounts dissolve in organic solvents such as ethanol, methanol, andchloroform. Depending on the medium used the dissolved substance is moreor less instable. Said instability is also a consequence of an oxidativedegradation of budesonide. Thus, without any further measure thegenerally known application of lipid-containing or water-soluble basesis not an option for the manufacture of stable and compatible budesonidesuppositories, since the medicinally effective component dissolved inthose vehicles is rapidly degraded.

As described in example 1, simple budesonide suppositories of solid fatof different quality (Witepsol® H15, Witepsol® W45) already after a 3months storage at 25° C./60% relative humidity show a ca. 10% reductionin content. Blends of budesonide with macrogols are per se incompatibledue to the peroxides inherently present in traces or formed in thismatrix, respectively, and do not represent an alternative for thetreatment of inflammatory diseases of the rectum because of the localirritation of the mucosa said suppositories cause after application.

In comparison, the budesonide suppositories according to the inventiondo not show the drawbacks underlying the prior art. The presentinvention is only made possible by a combination of measures, i. e. atleast two, preferably at least three of the measures listed below, eachof which is not sufficient to achieve the specified aim.

Thus, the object of the present invention are stable and compatiblebudesonide suppositories that can be obtained by the following measures:

-   (a) the use of budesonide as a medicinally effective component in a    suitable particle size distribution,-   (b) the choice of a suitable solid fat quality,-   (c) the addition of ascorbyl palmitate as an antioxidant to the    solid fat basis in an optimized concentration,-   (d) the adjustment of an optimum ratio of budesonide dissolved as    well as suspended in the solid fat basis,-   (e) the use of a suppository form and size, respectively, suitable    for the described application; and-   (f) the use of a cast film of low oxygen permeability as a package.

Preferably, two or more of said measures (i.e. 3, 4, 5, or 6) arecombined.

The budesonide suppositories composited and prepared in accordance withthe application according to the invention have sufficient stabilityallowing the storage and application of the suppositories atenvironmental conditions of 25° C./60% relative humidity for at least 24months. At the same time, it is ensured by the invention that theapplication of the suppositories for the treatment of the indicationaccording to the invention due to their size and form can be withoutpain and that, after the insertion of the suppositories, the proportionof suspended medicinally effective component rapidly sediments from themolten basis to the affected mucous membrane sites, while the dissolvedproportion is distributed from the basis. This ensures that bothpatient's compliance and efficacy of budesonide is made possible over asufficiently long period of time.

For the preparation of stable budesonide suppositories particularlysuitable are lipophilic bases of the solid fat type. Solid fat typeswith a high proportion of triglycerides (at least ca. 85%) and thus, lowhydroxyl value (5-15) have proved to be especially preferred. Solid fatsbasically consist of a mixture of different mono-, di-, andtriglycerides. Depending on the composition of the solid fat thisresults in a different number of free OH groups, which in turn resultsin different properties. Thus, one characteristic for solid fats is thehydroxyl value. Most important are solid fat types with hydroxyl values<15. Because of the small number of free OH groups there hardly occurincompatibilities with hydrolysis-sensitive substances or substanceswith free acid groups in those suppository bases. In comparison,generally solid fats with a high hydroxyl value have a goodemulsifiability and hardly any cracking during freezing. However, atendency to post-hardening can be observed and incompatibilities withthe active ingredient are possible. However, solid fats with a lowhydroxyl value of <15 have a low emulsifiability, more often tend tocracking during freezing and show low tendency to post-hardening.

According to the invention, preferably solid fat types are employedwhich contain as little or no unsaturated fatty acids as possible,because unsaturated compounds often are subject to oxidation reactionsand can rancidify. The number of unsaturated bonds in a lipid can beestablished by the iodine value (Ph. Eur. 2.5.4).

Solid fat consists of a blend of mono-, di-, and triglycerides. Byvariations in the composition and the esterified fatty acids the meltingpoint of the solid fat can be changed.

A preferably employed conventional type is Witepsol® H 15. Saidparticularly preferred quality mainly contains saturated fatty acids(iodine value ≤3), is characterized by a small distance between melting(33.5-35.5° C.) and freezing point (32.5-34.5° C.), and has only a lowtendency to post-hardening after pouring out. Using this basis ensuresthat the budesonide suppositories melt at body temperature and releasethe active ingredient.

It has surprisingly been shown that only a combination of activeingredient molecularly disperse dissolved as well as suspended in theparticularly preferred solid fat quality allows the manufacture ofstorage-stable budesonide suppositories. This optimized combination ofsolution and suspension preparation in a suppository permits thatfurther measures for stabilization only have to be limited to the solvedproportion of the active ingredient. As described in example 2, thesolubility of budesonide in the particularly preferred solid fat qualityWitepsol® H 15 is 1.5 mg/g. With this saturation concentration it ispossible to calculate the dose solubility of the active ingredient inthe basis and thus, to selectively choose the amount of antioxidantrequired for stabilization.

At a budesonide dose of 2 mg or 4 mg, respectively, and a suppositorymass of 1.8 g for the 2 mg form 100% of the dose are present molecularlydisperse dissolved (pure solution suppository), whereas for the 4 mgform the dissolved proportion is 67.5% (combined variant of solution andsuspension suppository).

Thus, preferably the weight ratio of budesonide to suppository mass (intotal) is between 1-10 to 1000 and particularly preferred between 1-5 to1000.

Only the reduction of the suppository mass from 1.8 g to 1 g that ispreferred according to the invention makes it possible to realize thecombined suppository variant for the desired dose range of 2 mg to 4 mg.In the case of the budesonide 2 mg suppositories then 75% of the doseare present in a dissolved form and 25% in a suspended form. For thebudesonide 4 mg suppositories the ratio is 37.5% (dissolved proportion)and 62.5% (suspended proportion). This ensures that an optimumconcentration of antioxidant can be added, which exerts the stabilizingeffect exclusively on the dissolved active ingredient proportion of37.5% to 75.0%. Only this surprisingly found complex interaction ofphysical and chemical stabilization of the preparation permits thelong-term stability of budesonide suppositories at environmentalconditions and thus, the renouncement of a storage in a refrigerator.

With the reduction of the mass from 1.8 g to about 1 g the budesonidesuppository at the same gets a size and shape that are particularlypreferred for the application so that insertion without any pain can beensured.

The suppositories according to the invention have a weight of about 0.8to 1.2 g, preferably 0.9 to 1.1 g, and particularly preferred 0.95 to1.05 g.

As described in example 1, the active ingredient proportion that ismolecularly disperse dissolved in the solid fat basis has to bestabilized by the addition of an anti-oxidatively acting excipient.Antioxidants are a group of excipients acting as free-radical scavengersor as substances that are easily oxidizable and thus, can protect theactive ingredient from oxidation.

Now it has been surprisingly found that only ascorbyl palmitate provesto be suitable for the stabilization among the antioxidants such asascorbyl palmitate, DL-a-tocopherol, and butylated hydroxyanisole thatare usually employed in non-aqueous, lipophilic systems. Example 3 showsthe results of the selection attempts. What is striking is that theexcipients DL-a-tocopherol, and butylated hydroxyanisole in contrast tothe actually desired anti-oxidative effect even enhance the degradationof budesonide in the solid fat basis.

The use of ascorbyl palmitate in a concentration range of 50 ppm to 250ppm has been shown to be particularly suitable. Example 4 shows theconcentration-related effect of ascorbyl palmitate on the contaminationprofile of budesonide 2 mg suppositories during a storage period of 24months at 25° C./60% relative humidity. In comparison to theunstabilized budesonide suppositories of example 1 only this measureallows a long-term stabilization of the active ingredient proportiondissolved in the solid fat, wherein preferably a concentration range of100 ppm to 200 ppm of ascorbyl palmitate is effective. With thedescribed reduction of the suppository mass to 1 g as well as theoptimized addition of ascorbyl palmitate of 100 ppm thus, budesonidesuppositories can be prepared that are stable for at least 24 months at25° C./60% relative humidity and do not need to be stored in arefrigerator.

In example 5 the composition of the preferred embodiments of budesonide2 mg and 4 mg suppositories is described. Here, the molten suppositorymass is poured into casting molds of plastic in which the masssubsequently rapidly solidifies. The dosage is volumetric for eachindividual suppository.

The laminated films used to receive the melt preferably consist of 100μm thick polyvinylchloride films (LDPE/PVC/PVdC) coated withpolyvinylidene chloride (40 g/m²) and polyethylene of low density (40μm). This casting mold is a package having an enhanced barrier functionagainst oxygen and represents an additional protective mechanism for theformulation. The barrier protection can still be enhanced when castingmolds of aluminum foil are selected for the budesonide suppositories.

In a preferred embodiment the suppositories according to the inventionare completely prepared under nitrogen atmosphere. This means, thatafter having composited the individual components of the finishedpharmaceutical formulation air is evacuated and subsequently, it isgassed with nitrogen or inert gas so that no oxidative reactions cantake place. Then, the molten suppository mass with active ingredient isdirectly brought into the prepared gas-tight laminated films where theyharden. Here, the laminated films are designed such that they prescribethe finished suppository shape and after being filled can be closed suchthat an oxygen contact with the suppository mass can largely be avoided.

By the measures according to the invention budesonide suppositories canbe prepared that are storage-stable at room temperature. The results ofthe shelf life tests of example 6 prove impressively that the selectedcombination of stabilizing measures and protective mechanisms makes itpossible to provide stable budesonide suppositories.

The particle size of the active ingredient budesonide should be as smallas possible. For that, the budesonide is micronized in a suitable mill(e.g. jet mill). According to the invention, the micronization iscarried out such that 100% of the particles are smaller than 10 μm. Themicronized budesonide is intermingled into the molten solid fat via thepowder feeding station of an inline homogenizer. Here, particleaggregates are milled and an even distribution of the undissolvedproportion of the active ingredient in the basis is achieved. Thereduction of the particle size is also a suitable means to preventactive ingredient sedimentation from the beginning. It is also importantthat the particles do not congregate. The risk of particle agglomerationis generally the larger the smaller the particles are, since with adecreasing particle size the surface area of the individual particlesincreases and thus, the surface energy increases. By adding a smallamount of surfactants (typically less than 0.5 wt %, based on themicronized budesonide preparation) the risk of particle growth can beprevented. The addition of a surfactant can also result in an improvedspreading and wetting of the active ingredient in the rectal fluid.However, it is important that a surfactant is chosen that does not causeany undesired side reaction in the administration of the suppositories.

For the therapeutic use the medicinally effective component budesonideis used in dosages of 2 mg to 4 mg. Here, the active ingredient is usedin the micronized form, wherein 100% of the particles are smaller than10 μm, at least 95% are smaller than 5 μm and at least 80% are smallerthan 3 μm. The determination of the particle size distribution ofbudesonide takes place by laser diffraction analysis (laserdiffractometry). Here, budesonide is wet-dispersed in an aqueous medium.After radiation of the particles with a monochromatic laser light thediffraction pattern is determined from which subsequently the particlesize distribution can be calculated. The use of a micronized qualityprevents the sedimentation of suspended budesonide in the moltensuppository mass during the manufacture and thus, permits the evenactive ingredient distribution in the poured out and frozen molds. Atthe same time the micronization increases the dissolution rate of thebudesonide, which has sedimented to the mucosa, in the rectal fluidafter inserting and melting of the suppositories. Example 7 shows theresults of in vitro releasing tests of budesonide 2 mg suppositoriesover a period of 2 hours. Within this period, both the suspendedproportion of the active ingredient and that dissolved in the solid fatbasis is released. Thus, with the formulation according to the inventionit is ensured that the entire budesonide dose is released from theformulation and is available over a sufficiently long period of time onthe rectal mucosa and thus, a therapeutic effect is achieved.

The suppositories according to the invention are preferably used for thetreatment of inflammatory diseases of the rectum. These are preferablyacute diseases for which a rapid relief of the symptoms is desirable.

The suppositories according to the invention are preferably used for thetreatment of patients with active ulcerative proctitis. In a preferredembodiment a suppository with 2 mg budesonide or a suppository with 4 mgbudesonide is administered once in the morning and once in the evening.Thus, the budesonide suppositories according to the invention areparticularly suitable for the treatment of active ulcerative proctitis.

In a clinical study on patients with acute ulcerative proctitis in whichembodiments of the present invention were studied alone or ascombination therapy with conventional mesalazine suppositories incomparison to conventional mesalazine suppositories it could bedemonstrated that the use of the budesonide suppositories according tothe invention led to a significant reduction in the time until clinicalsymptoms disappeared. This end point was defined in the clinical studyas the first day of three consecutive days with a point score of 0 forrectal bleeding and the frequency of defaecation.

The rate of patients that showed a clinical and endoscopic remission oran improvement in their symptoms was higher in those treated withbudesonide suppositories. Clinical and endoscopic remission was achievedwhen the patients in the modified DAI-UC index (Disease ActivityIndex-Ulcerative Colitis) had a value of ≤1, wherein the result in thecategories rectal bleeding and frequency of defaecation had to be 0 andat least 1 point of reduction in the sub-category “appearance of themucosa” had to be achieved. An improvement of the symptoms required atleast a reduction of the total score of ≥3 points.

Handling of the budesonide suppositories according to the invention withreduced suppository mass in patients also achieved a higher tolerancecompared with mesalazine suppositories that were tested as comparativepreparation.

In a special embodiment of the present invention the budesonidesuppositories according to the invention are used during a combinationtherapy with mesalazine suppositories. Such a combination therapypreferably is that each in the morning there is administered abudesonide suppository and in the evening a mesalazine suppository orthat in the morning a mesalazine suppository is administered and in theevening a budesonide suppository.

To evaluate the efficacy of the suppositories the modified UC-DAIevaluation standard as by Kamm et al. (2007, Gastroenterology, 132, p.66-75) is used. It is explicitly referred to the table 1 disclosed thereand the relating definitions of the parameters.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the releasing profile of budesonide 2mg suppositories ofbatch V2042 after manufacture (T0) and after storage of 24 months at 25°C./60% relative humidity (T24).

Preferred embodiments of the present invention are illustrated by thefollowing examples.

EXAMPLE 1: INFLUENCE OF THE SOLID FAT TO THE DEGRADATION OF BUDESONIDEIN SOLID FAT OF DIFFERENT QUALITIES WITHOUT STABILIZATION

TABLE 1 Content [%] 3 months 3 months 25° C./ 30° C./ Ini- 60% rel. 65%rel. Batch Composition tially humidity humidity V1860 Budesonide   2 mg96.2 86.6 75.3 Witepsol ® H15 1798 mg Total: 1800 mg V1866 Budesonide  2 mg 94.4 77.5 70.2 Witepsol ® W45 1798 mg Total: 1800 mg

Without any further stabilizing measures budesonide 2 mg suppositoriesof the solid fat type are instable, wherein also the nature of the solidfat used has influence on the stability. Already after a storage periodof 3 months a reduction in content of 10% and more is shown at 25°C./60% relative humidity. Here, the stability of budesonide with thesolid fat type Witepsol® W45 is clearly less favorable than with thequality Witepsol® H15. Due to the small proportion of mono- anddiglycerides Witepsol® H15 has a low hydroxyl value, while Witepsol® W45has a higher proportion of mono- and diglycerides. Thus, for Witepsol®H15 there is reduced the possibility of an interaction between the freehydroxyl groups of the solid fat and the functional groups of the activeingredient molecule.

EXAMPLE 2: SATURATION SOLUBILITY OF BUDESONIDE IN THE SOLID FAT TYPEWITEPSOL® H15

The solubility of budesonide was determined in the molten Witepsol® H15at 40° C. Here, increasing amounts of budesonide were suspended in thesolid fat basis. After separation of the undissolved proportion andfreezing of the suppository mass the dissolved or undissolvedproportion, respectively, was determined with HPLC/UV as follows:

TABLE 2 Potency of the Proportion of Budesonide suppositories/dosagedissolved in Witepsol ® H15 1 mg Budesonide in 0.97 mg/g correspondingto 100% 1 g Witepsol ® H15 2 mg Budesonide in 1.47 mg/g corresponding to75% 1 g Witepsol ® H15 3 mg Budesonide in 1.64 mg/g corresponding to 55%1 g Witepsol ® H15 4 mg Budesonide in 1.65 mg/g corresponding to 42% 1 gWitepsol ® H15

Accordingly, the saturation concentration of budesonide in Witepsol® H15determined at 40° C. is ca. 1.5 mg/g. In a 1 g suppository with a dosageof 2 mg budesonide 75% of the active ingredient are molecularly dispersedissolved in the solid fat basis, with a dosage of 4 mg these are 55%.Thus, the budesonide suppositories according to the invention are ablend of a solution and a suspension preparation. Only the dissolvedproportion of budesonide has to be stabilized by the addition ofantioxidants.

To determine the saturation concentration of budesonide in Witepsol® H15a 1 g suppository was prepared with different budesonide dosages andleft for a period of 24 hours at 40° C. Subsequently, there wasperformed a centrifugation (10 minutes at 4000 rpm) to sedimentundissolved budesonide. Finally, the suppositories were hardened for 2hours in a refrigerator (2-8° C.). To determine the budesonideconcentration the suppositories were divided in two different ratios(lower part with suppository tip and upper part). The two parts wereindividually processed for HPLC assay and then analyzed. From theindividual weighed portions as well as the obtained content values thebudesonide concentration was calculated in mg/g. The dissolvedproportion of budesonide distributes homogenously in the suppositorybasis, while the undissolved proportion accumulates in the suppositorytip. Thus, the results of the budesonide assay in the upper part of thesuppositories represent the dissolved proportion of budesonide. Thesevalues are found in the table.

EXAMPLE 3: CHOICE OF A SUITABLE ANTIOXIDANT FOR THE STABILIZATION OFDISSOLVED BUDESONIDE IN THE SOLID FAT TYPE WITEPSOL® H15

For the selection attempts different antioxidants described in the priorart were tested. Here, budesonide 2 mg suppositories with a mass of 1.8g were used that contain the active ingredient completely dissolved inthe solid fat basis. The antioxidants were added in a concentration of100 ppm of the preparation. The control batch was free from antioxidant.As the casting molds laminated films consisting of polyvinylchloridefilms (PVC) coated with low density polyethylene (LDPE) were used thatdid not contain an additional barrier layer of polyvinylidene chloride(PVdC). The suppositories were stored at 30° C./65% relative humidityfor a period of 30 days. After preparation and storage the contaminationprofile of the budesonide suppositories was determined with HPLC/UV. Thefollowing two tables summarize the tested formulations as well as theresults.

TABLE 3 Batch: Composition: V1912 V1915 V1916 V1917 Budesonide,     2 mg    2 mg     2 mg     2 mg micronized¹ Ascorbyl 0.180 mg — — — Palmitate(100 ppm) DL-α- — 0.180 mg — — Tocopherol (100 ppm) Butylated — — 0.180mg — Hydroxy- (100 ppm) anisole Witepsol ® 1797.820 mg 1797.820 mg1797.820 mg 1798.000 mg H15 Suppository 1800.000 mg 1800.000 mg 1800.000mg 1800.000 mg Mass ¹Particle size distribution: 100% < 10 μm, ≥95% < 5μm, ≥80% < 3 μm

TABLE 4 Batch: V1912 V1915 V1916 (100 ppm (100 ppm (100 ppm V1917ascorbyl DL-α- butylated (control) palmitate) tocopherol hydroxyanisoleStorage 0 30 0 30 0 30 0 30 period at 30° C./65% rel. humidity in daysSum of 1.34 6.03 0.73 0.65 2.13 14.10 1.89 15.52 degradation products(%) Increase 4.69 — 11.97 13.63 during storage (%)

Without the addition of an antioxidant (control batch, batch V1917) abudesonide degradation of ca. 5% can be observed within 30 days at 30°C./65% relative humidity (see also example 1). The addition of 100 ppmDL-a-tocopherol and butylated hydroxyanisole does not lead to astabilization of the suppositories (see batches V1915 and V1916).Surprisingly, the degradation of the active ingredient in the presenceof these antioxidants even increases significantly. Thus,DL-a-tocopherol and butylated hydroxyanisole do not represent optionsfor the stabilization of the budesonide suppositories. In contrast,ascorbyl palmitate shows a significant anti-oxidative effect. During thestorage period no degradation of budesonide can be observed. Theexperiment is performed under conditions that are unfavorable for thebudesonide stability such as complete solubility of the activeingredient in the solid fat as well as the use of cast films without anyfurther oxygen barrier to be able to show the anti-oxidative effect ofascorbyl palmitate.

EXAMPLE 4: OPTIMUM CONCENTRATION OF ASCORBYL PALMITATE AS AN ANTIOXIDANTFOR THE STABILIZATION OF DISSOLVED BUDESONIDE IN THE SOLID FAT TYPEWITEPSOL® H15

The effect of ascorbyl palmitate as an antioxidant for the stabilizationof budesonide was tested with the following recipes of budesonide 2 mgsuppositories:

TABLE 5 Batch: Composition: V2035 V2034 V2036 Budesonide,     2 mg     2mg     2 mg micronized¹ Ascorbyl Palmitate 0.075 mg 0.100 mg 0.125 mg(75 ppm) (100 ppm) (125 ppm) Witepsol ® H15  997.925 mg  997.900 mg 997.875 mg Suppository Mass 1000.000 mg 1000.000 mg 1000.000 mg¹Particle size distribution: 100% < 10 μm, ≥95% < 5 μm, ≥80% < 3 μm

Thus, for all suppositories the proportion of budesonide dissolved inthe solid fat basis and to be stabilized is 75%. As the casting moldslaminated films of LDPE/PVC/PVdC were used. After manufacture andstorage of 24 months at 25° C./60% relative humidity the contaminationprofile of the budesonide suppositories was determined with HPLC/UV. Theresults obtained were as follows:

TABLE 6 Batch: V2035 V2034 V2036 (75 ppm (100 ppm (125 ppm ascorbylascorbyl ascorbyl palmitate) palmitate) palmitate) Storage Period in 024 0 24 0 24 Months Sum of Degradation 0.19 2.93 0.16 2.17 0.19 1.70Products (%) Increase during 2.74 2.01 1.51 Storage (%)

Ascorbyl palmitate stabilizes the budesonide molecularly dispersedissolved in the solid fat basis depending on the concentration. Thepreferred embodiment of budesonide 2 mg and 4 mg suppositories containsascorbyl palmitate in a concentration range of 100 ppm to 150 ppm.

EXAMPLE 5: QUALITATIVE AND QUANTITATIVE COMPOSITION OF THE PREFERREDEMBODIMENTS OF BUDESONIDE 2 MG AND 4 MG SUPPOSITORIES

TABLE 7 Composition Budesonide, micronized¹     2 mg     4 mg AscorbylPalmitate 0.10-0.15 mg 0.10-0.15 mg (100-150 ppm) (100-150 ppm)Witepsol ® H15 997.85-997.900 mg 995.85-995.90 mg Suppository Mass1000.00 mg 1000.00 mg Casting Mold cast film of cast film ofLDPE/PVC/PVdC LDPE/PVC/PVdC ¹Particle size distribution: 100% < μm, ≥95%< 5 μm, ≥80% < 3 μm

EXAMPLE 6: SHELF LIFE TESTS OF THE PREFERRED EMBODIMENTS OF BUDESONIDE 2MG AND 4 MG SUPPOSITORIES

Budesonide 2 mg and 4 mg suppositories were prepared in the preferredembodiment with 100 ppm ascorbyl palmitate and stored at 25° C./60%relative humidity for shelf life tests. After manufacture and in regularintervals during the storage the content and the purity of thesuppositories were determined with HPLC/UV. The two following tablessummarize the results for budesonide 2 mg suppositories and budesonide 4mg suppositories.

TABLE 8 Budesonide 2 mg Suppositories with 100 ppm Ascorbyl Palmitate,Batch V2042 Storage Period (Months) at 25° C./60% rel. Humidity 0 3 6 912 18 24 Content of 99.5 97.3 96.2 96.5 96.0 95.0 96.6 Budesonide (%)Sum of Degradation 0.16 0.09 0.16 0.27 0.36 0.72 0.86 Products (%)

TABLE 9 Budesonide 4 mg Suppositories with 100 ppm Ascorbyl Palmitate,Batch V2043 Storage Period (Months) at 25° C./60% rel. Humidity 0 3 6 912 18 24 Content of 99.4 99.0 99.6 99.6 98.0 98.0 97.6 Budesonide (%)Sum of Degradation 0.10 0.10 0.10 0.16 0.24 0.38 0.38 Products (%)

The budesonide content and the sum of degradation products change onlyslightly during storage. With the surprisingly found combination ofphysical and chemical stabilization the shelf life of the budesonide 2mg and 4 mg suppositories is ensures for a period of at least 24 monthsat 25° C./60% relative humidity.

EXAMPLE 7: IN VITRO RELEASING TESTS OF BUDESONIDE 2 MG SUPPOSITORIES

The budesonide suppositories composited and prepared according to theinvention release the active ingredient over a period of 2 hours. Withinthis period, both the proportion of the active ingredient that issuspended and present in a micronized form and the proportion that ismolecularly disperse dissolved in the solid fat basis is released. Thisensures that the active ingredient is available over a sufficiently longperiod of time on the rectal mucosa and can exert its therapeuticeffect. FIG. 1 shows the releasing profile of budesonide 2 mgsuppositories of batch V2042 after manufacture (TO) and after storage of24 months at 25° C./60% relative humidity (T24). The determination takesplace at 37° C., preferably with the flow cell described in the EuropeanPharmacopoeia (apparatus 4), that is operated with a flow rate of 16ml/min as a closed system. Citric acid phosphate buffer pH 6.8 with anaddition of 0.5% of sodium dodecyl sulphate is used as the medium. Inorder to be able to describe the releasing kinetics sampling isperformed after 15, 30, 45, 60, 90, and 120 minutes. The budesonidedissolved in the release medium is determined with HPLC/UV.

EXAMPLE 8: EXAMINATION OF THE CLINICAL EFFICACY AND ACCEPTANCE OF THESUPPOSITORIES BY PATIENTS

During a double blind study budesonide suppositories were tested onpatients suffering from proctitis. 79 patients in total were treated,wherein different suppositories with different active ingredients weretested without the patients knowing exactly which suppository theyreceived.

During these tests it was found after which period of time a clinicalremission, defined as “first day”, with ≤3 defaecations/day, wherein allhad to be without blood in the feces, was observed. With thesuppositories according to the invention this period was 8 days inmedian terms.

As a further parameter there was determined the percentage of patientsthat showed a mucosal healing, wherein this was determined via endoscopyof the affected section of the intestine and was measured as thecorresponding part of a disease activity index (modifiedUC-DAI/Ulcerative Colitis-Disease Activity Index). Said value was 81%.The results obtained with budesonide suppositories according to theinvention with 4 mg of active ingredient (1 g total weight) aresummarized in table 10 below.

TABLE 10 Efficacy Parameter Clinical Remission, defined as first daywith ≤3 defaecations/day and all without blood in the feces RequiredTime of Treatment 8 days Mucosal Healing Endoscopy of the affectedsection of the intestine, measured as the corresponding part of adisease activity index (modified UC-DAI/Ulcerative Colitis-DiseaseActivity Index) N/N (%) 64/79 (81.0%)

As a further essential aspect that just with suppositories plays animportant role there was examined the acceptance of the suppositoriesaccording to the invention in patients. Here, data were collected via acorresponding questionnaire, wherein application of the suppositories inthe morning and impairment were queried. To the first question, “How doyou assess the use of suppositories in the morning?” patients couldanswer with “easy/not too arduous/difficult”. To the second question,“How much did using suppositories in the morning impair your dailyroutine?” the patients could answer with “considerable/not toomuch/nearly not at all”.

The results of the patient survey are summarized in table 11 below.

TABLE 11 Patient Acceptance Application of the easy not too difficult noSuppositories in the arduous statement Morning N/N (%) 62/79 (78.5)12/79 (15.2) 2/79 (2.5) 3/79 (3.8) Impairment of the nearly not not tooconsid- no everyday life by the at all much erable statement Applicationof the Suppositories in the Morning N/N (%) 46/79 (58.2) 26/79 (32.9)4/79 (5.1) 3/79 (3.8)

In summary, it can be concluded that a majority of the patients (78.5%)judged the application in the morning as easy and simple. Moreover, themajority of the patients (58.2%) found almost no impairment of theeveryday life by the application of the suppositories in the morning.

These data show that the suppositories according to the invention arenot only storage-stable, but also have a very good clinical efficacywith simultaneous high acceptance by the patients.

The invention claimed is:
 1. A pharmaceutical formulation for rectaladministration, containing about 2 mg budesonide or a pharmaceuticallycompatible salt or derivative thereof, and about 1000 mg of a solid fator a mixture of different solid fats, based on the total weight of theformulation, wherein the solid fat or mixture of different solid fatscomprises at least 80 wt % triglycerides, a hydroxyl value of 1 to 15and less than 1 wt % of unsaturated fatty acids, as well as at least oneanti-oxidation agent is the amount of about 100 ppm that is compatibletherewith, characterized in that the anti-oxidation agent is ascorbylpalmitate, and wherein the formulation contains no 5-aminosalicyclicacid, and when stored at 30° C./65% humidity for a period of 30 daysshowed no degradation.
 2. The formulation according to claim 1,characterized in that it has a small distance between melting andfreezing point, wherein the melting point is between 33.5° C. and 35.5°C. and the freezing point is between 32.5° C. and 34.5° C.
 3. Theformulation according to claim 1, characterized in that the solid fathas a high proportion of triglycerides, namely ≥90 wt %, a hydroxylvalue of 1 to 15 and contains less than 1 wt % of unsaturated fattyacids.
 4. The formulation according to claim 1, characterized in that itis a suppository for anal administration.
 5. The formulation accordingto claim 1, characterized in that the ascorbyl palmitate is present in aconcentration of 50 ppm to 200 ppm.
 6. The formulation according toclaim 1, characterized in that the budesonide is present in a micronizedform, wherein 100% of the particles are smaller than 10 μm per particle.7. The formulation according to claim 1, characterized in that thestorage-stable pharmaceutical formulation was prepared under exclusionof oxygen.
 8. The formulation according to claim 1, characterized inthat the pharmaceutical formulation is packaged in the form ofsuppositories in a gas-tight cast film.